Method and apparatus for producing homogenous cavitation to enhance transdermal transport

ABSTRACT

The present invention is directed to apparatus and methods for producing homogenous cavitation. An ultrasound souce comprising an ultrasound transmitting element having an axis and a cross-section along the axis is disclosed The ultrasound transmitting element also has a first axial end and a second axial end operable to produce ultrasonic waves. The cross-section has an area having a maximum value at the first axial end and a minimum value at the second axial end. A method for producing homogenous cavitation at an area of skin comprises creating a volume of fluid having a uniformly dispersed concentration of cavitation nuclei adjacent the area of skin. Ultrasound is then applied to the volume of fluid and causes cavitation at the cavitation nuclei.

FIELD OF THE INVENTION

[0001] This invention relates to transdermal molecular transportation.More specifically, this invention relates to methods and apparatus forproducing homogenous cavitation in a transdermal transport system.

BACKGROUND OF THE INVENTION

[0002] Drugs are routinely administered either orally or by injection.The effectiveness of most drugs relies on achieving a certainconcentration in the bloodstream. Although some drugs have inherent sideeffects which cannot be eliminated in any dosage form, many drugsexhibit undesirable behaviors that are specifically related to aparticular route of administration. For example, drugs may be degradedin the GI tract by the low gastric pH, local enzymes or interaction withfood or drink within the stomach. The drug, or disease itself mayforestall or compromise drug absorption because of vomiting or diarrhea.If a drug entity survives its trip through the GI tract, it may facerapid metabolism to pharmacologically inactive forms by the liver, thefirst-pass effect. Sometimes the drug itself has inherent undesirableattributes such as a short half-life, high potency or a narrowtherapeutic blood level range.

[0003] Recently, efforts aimed at eliminating some of the problems oftraditional dosage forms involve transdermal delivery of the drugs(TDD). Topical application has been used for a very long time, mostly inthe treatment of localized skin diseases. Local treatment, however, onlyrequire that the drug permeate the outer layers of the skin to treat thediseased state, with little or no systemic accumulation. Transdermaldelivery systems are designed for, inter alia, obtaining systemic bloodlevels, and topical drug application. For purposes of this application,the word “transdermal” is used as a generic term to describe the passageof substances to and through the skin.

[0004] TDD offers several advantages over traditional delivery methodsincluding injections and oral delivery. When compared to oral delivery,TDD avoids gastrointestinal drug metabolism, reduces first-pass effects,and provides sustained release of drugs for up to seven days, asreported by Elias in Percutaneous Absorption: Mechanism-Methodology-DrugDelivery, Bronaugh, R. L. Maibach, H. I. (Ed), pp 1-12, Marcel Dekker,New York, 1989.

[0005] The transport of drugs through the skin is complex since manyfactors influence their permeation. These include the skin structure andits properties, the penetrating molecule and its physical-chemicalrelationship to the skin and the delivery matrix, and the combination ofthe skin, the penetrant, and the delivery system as a whole.Particularly, the skin is a complex structure. There are at least fourdistinct layers of tissue: the nonviable epidermis (stratum corneum, SC)the viable epidermis, the viable dermis, the subcutaneous connectivetissue. Located within these layers are the skin's circulatory system,the arterial plexus, and appendages, including hair follicles, sebaceousglands, and sweat glands. The circulatory system lies in the dermis andtissues below the dermis. The capillaries do not actually enter theepidermal tissue but come within 150 to 200 microns of the outer surfaceof the skin.

[0006] In comparison to injections, TDD can reduce or eliminate theassociated pain and the possibility of infection. Theoretically, thetransdermal route of drug administration could be advantageous in thedelivery of many therapeutic drugs, including proteins, because manydrugs, including proteins, are susceptible to gastrointestinaldegradation and exhibit poor gastrointestinal uptake, proteins such asinterferon are cleared rapidly from the blood and need to be deliveredat a sustained rate in order to maintain their blood concentration at ahigh value, and transdermal devices are easier to use than injections.

[0007] In spite of these advantages, very few drugs and no proteins orpeptides are currently administered transdermally for clinicalapplications because of the low skin permeability to drugs. This lowpermeability is attributed to the SC, the outermost skin layer whichconsists of flat, dead cells filled with keratin fibers (keratinocytes)surrounded by lipid bilayers. The highly-ordered structure of the lipidbilayers confers an impermeable character to the SC (Flynn, G. L., inPercutaneous Absorption: Mechanisms-Methodology-Drug Delivery.;Bronaugh, R. L., Maibach, H. I. (Ed), pages 27-53, Marcel Dekker, NewYork 1989). Several methods have been proposed to enhance transdermaldrug transport, including the use of chemical enhancers, i.e. the use ofchemicals to either modify the skin structure or to increase the drugconcentration in a transdermal patch (Burnette, R. R., in DevelopmentalIssues and Research Initiatives; Hadgraft J., Guy, R. H., Eds., MarcelDekker: 1989; pp. 247-288; Junginger, et al. in Drug PermeationEnhancement; Hsieh, D. S., Eds., pp.59-90; Marcel Dekker, Inc. New York1994) and the use of applications of electric fields to create transienttransport pathways [electroporation] or to increase the mobility ofcharged drugs through the skin (iontophoresis) (Prausnitz Proc. Natl.Acad. Sci. USA 90, 10504-10508 (1993); Walters, K. A., in TransdermalDrug Delivery: Developmental Issues and Research Initiatives, Ed.Hadgraft J., Guy, R. H., Marcel Dekker, 1989). Another approach that hasbeen explored is the application of ultrasound.

[0008] Ultrasound has been shown to enhance transdermal transport oflow-molecular weight drugs (molecular weight less than 500) across humanskin, a phenomenon referred to as sonophoresis (Levy, J. Clin. Invest.1989, 83, 2974-2078; Kost and Langer in “Topical drug Bioavailability,Bioequivalence, and Penetration”; pp: 91-103, Shah V. P., Maibach H. I.Eds. (Plenum: New York, 1993); Frideman, R. M., “Interferons: A Primer”,Academic Press, New York, 1981) For example, U.S. Pat. No. 4,309,989 toFahim and U.S. Pat. No. 4,767,402 issued to Kost et al. both describethe use of ultrasound in conjunction with transdermal drug delivery.U.S. Pat. No. 4,309,989 discloses the topical application of amedication using ultrasound with a coupling agent such as oil.Ultrasound at a frequency of at least 1000 kHz and a power of one tothree W/cm² was used to cause selective localized intracellularconcentration of a zinc containing compound for the treatment of herpessimplex virus.

[0009] U.S. Pat. No. 4,309,989, the disclosure of which is specificallyincorporated by reference, discloses the use of ultrasound for enhancingand controlling transdermal permeation of a molecule, including drugs,antigens, vitamins, inorganic and organic compounds, and variouscombinations of these substances, through the skin and into thecirculatory system. Ultrasound having a frequency between about 20 kHz.and 10 MHz. and having an intensity between about 0 and 3 W/cm² is usedessentially to drive molecules through the skin and into the circulatorysystem. A significant drawback to this system is that the resultantenhanced permeability only occurs while the ultrasound is being appliedto the skin. Thus, the skin is often damaged due to over exposure to theultrasound.

[0010] Although a variety of ultrasound conditions have been used forsonophoresis, the most commonly used conditions correspond totherapeutic ultrasound (frequency in the range of between one MHz andthree MHz, and intensity in the range of between above zero and twoW/cm²) (such as that described in the Kost et al. patent). It is acommon observation that the typical enhancement induced by therapeuticultrasound is less than ten-fold. In many cases, no enhancement oftransdermal drug transport has been observed upon ultrasoundapplication. Accordingly, a better selection of ultrasound techniques isneeded to induce a higher enhancement of transdermal drug transport bysonophoresis.

[0011] Application of low-frequency (between approximately 20 and 200kHz) ultrasound can dramatically enhance transdermal transport of drugs,as described in PCT/US96/12244 by Massachusetts Institute of Technology.Transdermal transport enhancement induced by low-frequency ultrasoundwas found to be as much as 1000-fold higher than that induced bytherapeutic ultrasound. Another advantage of low-frequency sonophoresisas compared to therapeutic ultrasound is that the former can inducetransdermal transport of drugs which do not passively permeate acrossthe skin.

[0012] In addition to there being a need to deliver drugs through theskin, there is a major medical need to extract analytes through theskin. For example, it is desirable for diabetics to measure bloodglucose several times per day in order to optimize insulin treatment andthereby reduce the severe long-term complications, of the disease.Currently, diabetics do this by pricking the highly vascularizedfingertips with a lancet to perforate the skin, then milking the skinwith manual pressure to produce a drop of blood, which is then assayedfor glucose using a disposable diagnostic strip and a meter into whichthis strip fits. This method of glucose measurement has the majordisadvantage that it is painful, so diabetics do not like to obtain aglucose measurement as often as is medically indicated.

[0013] Therefore, many groups are working on non-invasive and lessinvasive means to measure glucose, such as micro lancets that are verysmall in diameter, very sharp, and penetrate only to the interstitium(not to the blood vessels of the dermis). A small sample, from about 0.1to two μl, of interstitial fluid is obtained through capillary forcesfor glucose measurements. Other groups have used a laser to breach theintegrity of the stratum corneum and thereby make it possible for bloodor interstitial fluid to diffuse out of such a hole or to be obtainedthrough such a hole using pneumatic force (suction) or other techniques.An example of such a laser based sampling device is disclosed in U.S.Pat. No. 5,165,418 to Tankovich and WPI ACC No: 94-167045/20 by Budnik(assigned to Venisect, Inc.).

[0014] A problem with methods that penetrate the skin to obtaininterstitial fluid is that interstitial fluid occurs in the body in agel like form with little free fluid and in fact is even negativepressure that limits the amount of free interstitial fluid that can beobtained. When a very small hole is made in the skin, penetrating to adepth such that interstitial fluid is available, it takes a great dealof mechanical force (milking, vacuum, or other force) to obtain thequantity of blood used in a glucose meter.

[0015] Thus, there has been described methods for application ofultrasound and extraction of analyte that rely on techniques known inthe art such as are disclosed in U.S. patent application Ser. No.08/885,931 filed Jun. 30, 1997, the disclosure of which is herebyincorporated by reference. The methods described therein channel orfocus an ultrasound beam onto a small area of skin. In some embodiments,methods and devices utilizing a chamber and ultrasound probe disclosedcan be used to non-invasively extract analyte and deliver drugs (i.e,broadly transdermally transport substances). This provides manyadvantages, including the ability to create a small puncture orlocalized erosion of the skin tissue, without a large degree ofconcomitant pain. The number of pain receptors within the ultrasoundapplication site decreases as the application area decreases. Thus, theapplication of ultrasound to a very small area will produce lesssensation and allow ultrasound and/or its local effects to beadministered at higher intensities with little pain or discomfort.Channeling of ultrasound geometrically is one way to apply ultrasound toa small area. The oscillation of a small element near or in contact withthe surface of the skin is another way to apply ultrasound to a smallarea. Large forces can be produced locally, resulting in cavitation,mechanical oscillations in the skin itself, and large localized shearingforces near the surface of the skin. The element can also produceacoustic streaming, which refers to the large convective flows producedby ultrasound. This appears to aid in obtaining a sample of blood orinterstitial fluid without having to “milk” the puncture site.Ultrasound transducers are known to rapidly heat under continuousoperation, reaching temperatures that can cause skin damage. Heat damageto the skin can be minimized by using a transducer that is located awayfrom the skin to oscillate a small element near the skin. In the case ofanalyte extraction, compounds present on the surface of and/or in theskin can contaminate the extracted sample. The level of contaminationincreases as skin surface area increases. Surface contamination can beminimized by minimizing the surface area of ultrasound application.Thus, skin permeability can be increased locally, and transientlythrough the use of the methods and devices described herein, for eitherdrug delivery or measurement of analyte.

[0016] Moreover, it has been disclosed that the application ofultrasound is only required once for multiple deliveries or extractionsover an extended period of time rather than prior to each extraction ordelivery. That is, it has been shown that if ultrasound having aparticular frequency and a particular intensity of is applied, multipleanalyte extractions or drug deliveries maybe performed over an extendedperiod of time. For example, if ultrasound having a frequency of 20 kHz.and an intensity of 10 W/cm² is applied, the skin retains an increasedpermeability for a period of up to four hours. This is described moreparticularly in United States Provisional Patent Application No.60/070,813 filed on Jan. 8, 1998, the disclosure of which isspecifically incorporated by reference herein.

[0017] Nevertheless, the amount (e.g., duration, intensity, duty cycleetc.) of ultrasound necessary to achieve this permeability enhancementvaries widely. Several factors on the nature of skin must be considered.For example, the type of skin which the substance is to pass throughvaries from species to species, varies according to age, with the skinof an infant having a greater permeability than that of an older adult,varies according to local composition, thickness and density, varies asa function of injury or exposure to agents such as organic solvents orsurfactants, and varies as a function of some diseases such as psoriasisor abrasion.

[0018] When cavitation is relied upon to enhance transdermal transport,care must be taken to avoid excessive cavitation which can do damage tothe skin through the localized increases of heat and pressurecharacteristic with cavitation phenomena. If the cavitation produced issporadic or nonuniform, it very difficult to prevent the localized heatand pressure increases.

SUMMARY OF THE INVENTION

[0019] Therefore, a need has arisen for a method and apparatus thatprovides homogenous cavitation for use in a transdermal transportsystem.

[0020] According to one embodiment, the present invention comprises animproved ultrasound source. The ultrasound source comprises anultrasound transmitting element having an axis and a first cross-sectionalong said axis. The ultrasound transmitting element also has a firstaxial end operable to produce ultrasonic waves and a second axial end.The first axial end comprises a matrix of ultrasound producing portions.

[0021] According to another embodiment, the present invention comprisesan ultrasound source. The ultrasound source comprises an ultrasoundtransmitting element having an axis and a cross-section along the axis.The ultrasound transmitting element also has a first axial end and asecond axial end operable to produce ultrasonic waves. The cross-sectionhas an area having a maximum value at the first axial end and a minimumvalue at the second axial end.

[0022] According to another embodiment, the present invention comprisesa method for producing homogenous cavitation at an area of skin. Themethod comprises creating a volume of fluid having a uniformly dispersedconcentration of cavitation nuclei adjacent the area of skin. Ultrasoundis then applied to the volume of fluid and causes cavitation at thecavitation nuclei.

[0023] According to another embodiment, the present invention comprisesa method for producing homogenous cavitation at an area of skin. Themethod comprises creating a volume of fluid having a uniformly dispersedconcentration of a first substance adjacent the area of skin. The firstsubstance is a substance that facilitates the production of cavitation.Ultrasound is then applied to the volume of fluid to cause cavitation.

[0024] According to another embodiment, the present invention comprisesa method for producing homogenous cavitation at an area of skin. Anultrasound source is provided to apply an ultrasonic wave to the area ofskin. A screen having a number of opening therein is positioned betweenthe area of skin and the ultrasound source. Finally, ultrasound isapplied to the area of skin through the screen. The openings in thescreen nucleate cavitation and control the size of cavitation bubblesproduced.

[0025] According to another embodiment, the present invention comprisesan ultrasound device. The ultrasound device includes an ultrasound hornand a housing for the ultrasound horn. The housing has a portion with areduced inside diameter relative to a diameter of the horn. The reducedinside diameter focuses ultrasonic energy on a

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The features and objects of the present invention, and the mannerof attaining them is explained in detail in the following DETAILEDDESCRIPTION OF THE PREFERRED EMBODIMENTS of the invention when taken inconjunction with the accompanying drawings wherein:

[0027]FIGS. 1a and 1 b depict an ultrasonic horn configuration accordingto one embodiment of the present invention.

[0028]FIGS. 2a-2 d depict an ultrasonic horn configuration according toanother embodiment of the present invention.

[0029]FIGS. 3a and 3 b depict an ultrasonic horn configuration accordingto another embodiment of the present invention.

[0030]FIG. 4 depicts an ultrasound configuration according to anotherembodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The use of ultrasound to facilitate transdermal transport isknown. The mechanism by which ultrasound is used to facilitatetransdermal transport has differed. In the context of transdermaldelivery systems, ultrasound was initially used as a driving force thatessentially pushed drugs through the skin and into the circulatorysystem. Ultrasound is also used to increase the permeability of theskin. That is, application of ultrasound having a particular frequencywill disorganize the lipid bilayer in the skin and thus increase thepermeability of the skin. In this context, either drugs can be deliveredthrough the skin to the body or analyte can be extracted through theskin from the body. A driving force of some type is still required, butthe required intensity of the driving force is decreased. For example, aconcentration gradient is generally sufficient driving force fortransdermal transport through skin whose permeability, as been enhancedusing ultrasound.

[0032] The permeability enhancement that results from the application ofultrasound is due, at least in part, to cavitation that is caused by theultrasound. When used to irradiate liquid medium such as the couplingmedium used in conjunction with the present invention, certainultrasonic fields will cause cavitation in the liquid. Broadly defined,cavitation is the formation of vapor or gas filled cavities in liquidswhen subjected to mechanical forces. One problem with being able toeffectively use cavitation to enhance skin permeability is thatcavitation is not readily predictable or controllable. In the context ofa transdermal delivery system, cavitation that is inconsistent andunevenly dispersed is not as effective at enhancing skin permeability ascavitation that is consistent and evenly dispersed. Moreover, cavitationthat is highly localized may cause skin damage. This applicationdescribes various apparatus and methods the inventors have found toproduce consistent, evenly dispersed cavitation.

[0033] Ultrasound is created and transmitted using a combination of atransducer and horn. The transducer, converts an electrical impulse intoa mechanical vibration and the horn transmits that mechanical vibrationto a medium. The configuration of the horn determines the wave patternof the ultrasound being transmitted to the medium. Moreover, the wavepattern of the ultrasound is, at least in part, responsible for thecavitation. Therefore, the horn configuration directly affects theamount and dispersement of the cavitation caused by an ultrasonic wave.The inventors have found a number of horn configurations that produce awave pattern that causes evenly dispersed and consistent cavitation.

[0034] According to one embodiment, the present invention comprises anultrasonic horn configuration including a number of ultrasound producingportions or “fingers” that produce evenly dispersed cavitation. As shownin FIG. 1, cylindrical shaped ultrasound horn 10 having an axis 5comprises a first axial end 1, a second axial end 2 and a plurality ofultrasound producing portions 3. Ultrasound horn 10 is generallyconnected to a transducer at its first axial end 1. The transducertransmits a vibration to horn 10 and the vibration is, in turn,transmitted to a fluid medium at second axial end 2 of horn 10.

[0035] Second axial end 2 of horn 10 is configured to include aplurality of ultrasound producing portions or fingers 3. Each ultrasoundproducing portion 3 produces a separate ultrasonic wave and therefore aseparate cavitation source. Moreover, in operation the ultrasonic waveproduced by each finger 3 is in phase with and overlaps with theultrasonic waves produced by its neighboring fingers. This overlapresults in more evenly distributed ultrasound that in turn leads to moreevenly distributed cavitation.

[0036] In the environment of an apparatus used to enhance thepermeability of the skin, ultrasound horn 10 is preferably configured sothat the more evenly distributed cavitation occurs at or near thesurface of the skin. This is accomplished by controlling the width ofeach finger, WF, the width of the gaps between the fingers, WG, and thedistance, D, between the second axial end of the horn and the skinsurface 4.

[0037] Ultrasound producing portions 3 can be fabricated on the end ofhorn 10 in a number of ways depending on the material used for horn 10.For example, if horn 10 is made of metal, fingers 3 may be configured onthe second axial end of horn 10 by making a number of cuts through horn10 in parallel with axis 5. These cuts can be made, for example, by andelectrical discharge manufacturing process. This can be used to producea matrix of ultrasound producing portions such as is shown in FIG. 1. Inother embodiments, ultrasound producing portions 3 are affixed to secondaxial end 2 of horn 10 by for example by press fitting the fingers intothe end of horn 10. The fingers are preferably made from a hard anddurable material such as titanium, and carbide steel. Other materialssuch as, stainless steel, aluminum, ceramic and glass could be used.

[0038] Horn 10 is shown as a cylindrical horn having ultrasoundproducing portions having a square cross-section along the horn axis.But, the horn and ultrasound producing portions could have manydifferent shapes and many different combinations of shapes. For example,the horn could be a bar shaped horn having a square cross-section andthe fingers could be cylindrical with a circular cross-section. Further,the number of fingers configured on the end of the horn can vary. Thenumber of fingers will determine the necessary dimensions WG and WF.

[0039] According to another embodiment, the present invention comprisesan ultrasonic horn having a “bullet” configuration that produces acavitation effect that spreads out over the surface of the skin 24. Asshown in FIG. 2, bullet shaped ultrasound horn 20 having an axis 25comprises a first axial end 21, a second axial end 22 having a taperedor bullet shaped configuration. Ultrasound horn 20 is generallyconnected to a transducer at its first axial end 21. The transducertransmits a vibration to horn 20 and the vibration is, in turn,transmitted to a fluid medium at second axial end 22 of horn 20.

[0040] Second axial end 22 of horn 20 is configured to include a bulletshape. That is, the cross-section along axis 25 of horn 20 varies insize between first axial end 21 and second axial end 22. Morespecifically, the axial cross-section has an area having a maximum valueat first axial end 21 and a minimum value at second axial end 22.Referring particularly to FIGS. 2b, 2 c and 2 d, various cross sectionsof horn 20 are shown. As is readily apparent, the area A is greater thanthe area A1, and the area A1 is greater than the area A2; A2 being thearea of the cross-section nearest the second axial end of horn 20 and Abeing the area of the cross-section nearest the first axial end of horn20. In operation, the ultrasonic wave produced by this bullet shapedconfiguration gradually spreads out as the distance from second axialend 22 increases and leads to cavitation that spreads out over skinsurface 24.

[0041] This extent of the spreading out effect can be optimized somewhatby controlling the rate of decrease of the cross-sectional area of horn20. In general, as the rate of area reduction increases, that is, horn20 becomes more tapered, the spreading effect becomes greater up to thepoint where second axial end 22 has a spherical configuration.

[0042] Horn 20 can be fabricated from any suitable material. The bulletconfiguration can be formed at second axial end of horn 20 using anysuitable machining process. For example, second axial end 22 can beturned on a lathe to the bullet configuration.

[0043] Horn 20 is shown as a cylindrical horn. Nevertheless, a similarspreading effect can be obtained by machining the bullet configurationat the second axial end of any horns. For example, a bar shaped hornhaving a square cross-section along the horn axis could be configuredwith a bullet shaped end.

[0044] According to another embodiment, the present invention comprisesan ultrasonic-horn that combines the beneficial features of the fingerhorn and bullet horn described in conjunction with FIGS. 1 and 2. Asshown in FIG. 3, ultrasound horn 30 having an axis 35 comprises a firstaxial end 31, a second axial end 32, and a plurality of ultrasoundproducing portions 33. Ultrasound horn 30 is generally connected to atransducer at its first axial end 31. The transducer transmits avibration to horn 30 and the vibration is, in turn, transmitted to afluid medium at second axial end 32 of horn 30.

[0045] Second axial end 32 of horn 30 is configured to include aplurality of ultrasound producing portions or fingers 33. Eachultrasound producing portion 33 has a tapered or bullet shapedconfiguration and generates a separate ultrasonic wave that produces acavitation effect that spreads out over the surface of the skin 34. Inoperation the ultrasonic wave produced by each finger 33 is in phasewith and overlaps with the ultrasonic waves produced by its neighboringfingers. This overlap results in more evenly distributed ultrasound thatin turn leads to more evenly distributed cavitation.

[0046] Each bullet shaped finger 33 has an axis 335 and a cross-sectionthat varies in size between a first axial end 331 and a second axial end332. More specifically, the axial cross-section has an area having amaximum value at first axial end 331 and a minimum value at second axialend 332. Horn 30 is depicted as having eighteen fingers only for ease ofillustration. In a preferred embodiment, horn 30 has a number of figuresnecessary to produce a desired cavitation pattern. According to oneembodiment, horn 30 is configured to have about 60 fingers.

[0047] In the environment of an apparatus used to enhance thepermeability of the skin, ultrasound horn 30 is preferably configured sothat the more evenly distributed cavitation occurs at or near thesurface of the skin. This is accomplished by controlling the width ofeach finger, WF, the width of the gaps between the fingers, WG, and thedistance, D, between the second axial end of the horn and the skinsurface 34.

[0048] Horn 30 is shown as a cylindrical horn. Nevertheless, horn 30 mayhave many different configurations. For example, bullet shaped fingerscould be a incorporated into a bar shaped horn having a squarecross-section. Further, the number of fingers configured on the end ofhorn 30 can vary. The number oft fingers will determine the necessarydimensions WG and WF.

[0049] Ultrasound transducers endure a great stress in normal operation.For example, cavitation can cause localized hot spots and high pressuregradients. Extended exposure to ultrasound and cavitation can causepitting of the ultrasound. Pitting of an ultrasound horn quickly leadsto accelerated decay, because the nonuniformities in the horn act ascavitation nuclei and therefore lead to cavitation occurring at thesurface of the horn. Moreover, when cavitation occurs at the surface ofthe horn, it interrupts further transmission of the ultrasonic wave andtherefore diminishes the amount of cavitation occurring elsewhere. Inthe context of an apparatus for enhancing skin permeability, this isdisadvantageous because it reduces the effectiveness of the ultrasound.Exposure times need to be increased to enhance permeability, thusincreasing the chance of over exposure to ultrasound.

[0050] Therefore, according to another embodiment, the present inventioncomprises a highly durable ultrasound horn. According to one embodimentthe present invention comprises an ultrasound horn comprised of acarbide steel tip. In another embodiment, the present inventioncomprises an ultrasound horn that has an anodized hard coating. The useof carbide steel is generally limited to the tip of the horn to minimizelosses. An anodized coating can be used on the entire horn or simply theultrasound radiating portion. The teachings of this embodiment of thepresent invention could be applied to any configuration of ultrasoundhorn including any of the horns shown and described in FIGS. 1-4. Forexample, in the context of FIG. 1, an improved ultrasound horn 10 isformed by fabricating ultrasound radiating portions 3 from carbidesteel. According to another example, an improved ultrasound horn 10 isformed by anodizing the entire horn to after fabrication. Both the useof an anodized coating or carbide steel provide an ultrasound hornhaving enhanced durability and resistance to, pitting.

[0051] Similarly, according to another embodiment, the present inventioncomprises a highly polished ultrasound horn. For reasons discussedabove, a highly polished ultrasound horn produces more consistent andhomogenous cavitation. By polishing the ultrasound horn, nonuniformitiesare removed from the surface of the horn. This, in turn, limits thechance of sporadic cavitation at the horn surface.

[0052] According to another embodiment, the present invention comprisesa method of producing consistent and evenly dispersed cavitation using acavitation screen. Structurally, the cavitation screen is a screen asthat term is conventionally used. That is, a cavitation screen accordingto embodiments of the present invention is a flat, planar object havinga matrix of openings therein. The cavitation screen is preferably formedfrom a durable and non-corrosive material such as metal. The cavitationscreen may also be treated or coated with durable coating so that it ismore resistant to the effects of ultrasound. For example, the screen maybe anodized.

[0053] Operationally, the cavitation screen is positioned between anultrasound horn and the object to which ultrasound is to be applied. Thecavitation screen enables transmission and growth of consistent bubbles.The openings in the screen nucleate cavitation and filter the bubblesproduced by cavitation. That is, cavitation bubbles may still beproduced throughout the liquid, but the screen acts to break the bubblesthat are larger than the size of the openings in the screen. The size ofthe openings can be adjusted to produce the cavitation desired. Further,in the context of an apparatus for enhancing skin permeability, thescreen may be positioned anywhere between the horn and the skin. If thescreen is positioned close to the horn, the cavitation will be somewhatseparated from the skin surface and have a lesser effect. If the screenis moved closer to the skin, the cavitation also occurs closer to theskin and therefore will have a more pronounced effect on skinpermeability.

[0054] According to another embodiment, the present invention comprisesa method of producing consistent and evenly, dispersed cavitation by“seeding” the coupling medium with cavitation nuclei. More,specifically, it has been found that the addition of particles to thecoupling medium used in an apparatus for enhancing skin permeabilityleads to more consistent cavitation. Each particle dispersed within thecoupling medium acts as a cavitation nuclei. Therefore, if particles areevenly dispersed throughout the coupling medium, more consistent andevenly dispersed cavitation results. The particles may be formed fromceramics, polystyrene, titanium dioxide or any other metal or polymer.The particles are sized appropriately for dispersion in the couplingmedium. In one embodiment, the particles are 1-20 μm in diameter.Smaller or larger sizes are possible. The concentration of particlesused should be appropriate for dispersion in the coupling medium. In oneembodiment 5-10 mg/ml of particles are used. The concentration ofparticles used varies depending on the type of particles used and thecoupling medium.

[0055] In a related embodiment, dissolved gas, such as O₂ is used in thecoupling medium to “seed” cavitation. If the dissolved gas is in theform of bubbles, these bubbles act as cavitation nuclei. If thedissolved gas exists at the molecular level, it diffuses into cavitationbubbles and enhances, growth. The cavitation enhancement is directlyproportional to the amount of dissolved gas in the medium. Therefore, bycontrolling the dissolved, gas concentration in the medium, the amountof cavitation produced by ultrasound can be controlled. Any suitable gasmay be used to enhance cavitation. Suitable gasses include, for example,oxygen, zenon, neon, argon, krypton and helium. If oxygen is used as thegas, a concentration of about 5 mg/dl is provided in the couplingmedium. Other concentrations are possible and within the scope of thepresent invention.

[0056] In another embodiment, the present invention comprises a methodfor producing consistent and evenly dispersed cavitation by dissolvingchemicals in the coupling medium. Certain chemicals, have propertiesthat are helpful for producing consistent cavitation. In one embodiment,fluorocarbons are added to the coupling medium in an attempt to producemore consistent cavitation. Fluorocarbons have a very low boiling point.Therefore, when fluorocarbons are subjected to ultrasound they tend toevaporate. This, evaporation causes gas bubbles in the coupling medium.These gas bubbles, in turn, act as cavitation nuclei and thus produceconsistent cavitation. The amount of fluorocarbon added to the couplingmedium can be adjusted based on the desired, amount of cavitation.Suitable fluorocarbons include, for example, perfluoropentane,perfluorohexane and similar molecules. In one embodiment, thefluorocarbons are used at a concentration of 5-10 mg/ml. Otherconcentrations are possible and within the scope of the presentinvention.

[0057] Similarly, surfactants can be added to the coupling medium toproduce more consistent cavitation by a different mechanism. The use ofsurfactants in the coupling medium does not, “seed” cavitation as theabove methods do. Rather, by adding surfactant to the coupling medium,the surface tension of the coupling medium is reduced. This reducedsurface tension makes it easier for cavitation to occur by making iteasier for bubbles to form in the medium. Suitable surfactants includesodium lauryl sulfate and fatty alcohols, for example, dodecanol.

[0058] In another embodiment, the present invention comprises a methodfor producing consistent and evenly dispersed cavitation by pretreatingthe skin with chemicals or cavitation nuclei. In one embodiment, theskin surface to be subjected to ultrasound is wiped with a chemicalcleansing agent that removes inhomogeneities from the skin surface. Theremoval of inhomogeneities from the skin surface leads to moreconsistent cavitation by removing substances that could act ascavitation nuclei and cause sporadic, localized cavitation that coulddamage the skin. Alhocols such as ethanol and isopropyl alcohol aresuitable for use to pretreat the skin.

[0059] In another embodiment, the skin to be treated with ultrasound ispresoaked with cavitation nuclei to produce more consistent cavitation.The cavitation nuclei could be in any of the forms discussed above.According to one embodiment, the skin is presoaked with solution havingevenly dispersed and very fine particles. The particles evenlydistribute themselves on the surface of the skin. This results inconsistent and evenly dispersed cavitation when ultrasound is applied.In another embodiment, the skin is presoaked with a liquid having a highdissolved gas content. Similar to above, when ultrasound is applied, thedissolved gas acts as cavitation nuclei and thus produces consistentcavitation.

[0060] Referring to FIG. 4, an ultrasound configuration according toanother embodiment of the present invention is provided. Ultrasonic horn40 may be used in conjunction with transducer housing 42 that has areduced inside diameter, relative to horn 40, where housing 42 is incontact with skin 44. Ultrasonic horn may be coupled with skin 44through coupling medium 46. The walls of reduced diameter housing 42mask a significant portion of skin 44, and expose only a fraction ofskin 44 to ultrasound.

[0061] The cavitation effect on the skin is generally most pronounced inthe center. Therefore, through this configuration, the level ofpermeability enhancement achieved is centralized of the treated skin.

[0062] Other methods, such as a pin horn and accoustic channeling, maybe used to produce a similar effect on the skin.

[0063] The above embodiments focus on methods and apparatus used toproduce consistent and homogenous cavitation. As will be apparent to oneof ordinary skill in the art, these methods are not mutually exclusive.The methods and apparatus can be combined to provide even greatercontrol of cavitation. For example, any of the horns shown in FIGS. 1-4can be used in conjunction with the addition of cavitation nuclei to thecoupling medium. Similarly, both chemicals and cavitation nuclei couldbe added to the coupling medium for an enhanced effect. The area of skincan be pretreated in conjunction with any of the above apparatus andmethods.

[0064] Although the present invention has been described in detail, itshould be understood that various changes, substitutions, andalterations can be made without departing from the intended scope asdefined by the appended claims.

1. An ultrasound source comprising: an ultrasound transmitting elementhaving an axis and a first cross-section along said axis, saidultrasound transmitting element having a first axial end and a secondaxial end, said first axial end operable to produce ultrasonic waves;and said first axial end comprising a matrix of ultrasound producingportions, said matrix having the first cross-section; wherein saidultrasound producing portions are formed by making a first series ofparallel axial cuts in the ultrasound transmitting element and a secondseries of parallel axial cuts in the ultrasound transmitting element,and wherein said first series of parallel axial cuts and said secondseries of parallel axial cuts are approximately perpendicular.
 2. Theultrasound source of claim 1 wherein said ultrasound transmittingelement comprises a cylindrical horn and said first cross-section is acircle.
 3. The ultrasound source of claim 1 wherein said ultrasoundtransmitting element comprises a flat horn and said first cross-sectionis rectangular.
 4. The ultrasound source of claim 3 wherein said matrixof ultrasound producing portions comprises a row of ultrasound producingportions.
 5. The ultrasound source of claim 1 wherein each one of saidultrasound producing portions has a first end proximal to the ultrasoundtransmitting element, a second end distal to the ultrasound transmittingelement and a cross-section.
 6. The ultrasound source of claim 5 whereinat least one of said ultrasound producing portions comprises across-section having an area with a maximum value at the first end andan area with a minimum value at the second end.
 7. The ultrasound sourceof claim 6 wherein at least one of said ultrasound producing portionshas a circular cross-section.
 8. The ultrasound source of claim 1wherein the first end radiates ultrasound toward a skin surface andcauses cavitation in the coupling medium, at the skin surface or in theskin.
 9. The ultrasound source of claim 1 wherein said first endcomprises an anodized coating.
 10. The ultrasound source of claim 1wherein said first end comprises carbide steel.
 11. The ultrasoundsource of claim 10 wherein said carbide steel fist end is bonded to saidultrasound transmitting element.
 12. An ultrasound source comprising: anultrasound transmitting element having an axis and a cross-section alongsaid axis, said ultrasound transmitting element having a first axial endand a second axial end, said second axial end operable to produceultrasonic waves; said cross-section having an area having a maximumvalue at the first axial end and a minimum value at the second axialend; and said first axial end comprising a matrix of ultrasoundproducing portions, said matrix having the first cross-section; whereinsaid ultrasound producing portions are formed by malting a first seriesof parallel axial cuts in the ultrasound transmitting element and asecond series of parallel axial cuts in the ultrasound transmittingelement, and wherein said first series of parallel axial cuts and saidsecond series of parallel axial cuts are approximately perpendicular.13. The ultrasound source of claim 12 wherein said cross-section has auniform shape and an area that decreases from a maximum value at thefirst axial end to a minimum value at the second axial end.
 14. Theultrasound source of claim 12 wherein said ultrasound transmittingelement has a circular cross-section along said axis.
 15. The ultrasoundsource of claim 12 wherein the ultrasound transmitting element producesan ultrasound wave pattern that produces uniformly distributedcavitation.
 16. The ultrasound source of claim 12 wherein the firstaxial end radiates ultrasound toward a skin surface and causes uniformlydistributed cavitation in the coupling medium, at the skin surface or inthe skin.
 17. The ultrasound source of claim 12 wherein said first endcomprises an anodized coating.
 18. The ultrasound source of claim 12wherein said first end comprises carbide steel.
 19. The ultrasoundsource of claim 18 wherein said carbide steel first end is bonded tosaid ultrasound transmitting element.
 20. A method for producinghomogenous cavitation at an area of skin comprising: creating a volumeof fluid adjacent the area of skin, said fluid having a uniformlydispersed concentration of cavitation nuclei therein; and applyingultrasound to the volume of fluid from an ultrasound transmittingelement having an axis and a cross-section along said axis, saidultrasound transmitting element having a first axial end and a secondaxial end, said second axial end operable to produce ultrasonic waves,said first axial end comprising a matrix of ultrasound producingportions, said matrix having the first cross-section, wherein saidultrasound producing portions are formed by making a first series ofparallel axial cuts in the ultrasound transmitting element and a secondseries of parallel axial cuts in the ultrasound transmitting element,and wherein said first series of parallel axial cuts and said secondseries of parallel axial cuts are approximately perpendicular; whereinthe ultrasound causes cavitation to begin at or around the cavitationnuclei.
 21. The method of claim 20 wherein the cavitation nucleicomprise appropriately sized ceramic particles.
 22. The method of claim20 wherein the cavitation nuclei comprise appropriately sized polymerparticles.
 23. The method of claim 20 wherein the cavitation nucleicomprise appropriately sized titanium dioxide particles.
 24. The methodof claim 20 wherein the cavitation nuclei comprises gas bubbles.
 25. Themethod of claim 20 further comprising delivering a substance through thearea of skin.
 26. The method of claim 20 further comprising extractinganalyte through the area of skin.
 27. A method for producing homogenouscavitation at an area of skin comprising: creating a volume of fluidadjacent the area of skin, said fluid having a uniformly dispersedconcentration of a fluorocarbon therein, said fluorocarbon facilitatingthe production of cavitation; and applying ultrasound to the volume offluid; wherein the ultrasound causes cavitation in the fluid,evaporation of the fluorocarbon and the creation of gas bubbles in thecoupling medium.
 28. The method of claim 27 further comprisingdelivering a substance through the area of skin.
 29. The method of claim27 further comprising extracting analyte through the area of skin.
 30. Amethod for producing homogenous cavitation at an area of skincomprising: creating a volume of fluid adjacent the area of skin, saidfluid having a uniformly dispersed concentration of a first substancetherein, said first substance facilitating the production of cavitation;applying ultrasound to the volume of fluid; wherein the ultrasoundcauses cavitation in the fluid; and wherein the first substance is asurfactant that facilitates the occurrence of cavitation when thecoupling fluid is exposed to ultrasound.
 32. The method of claim 30further comprising delivering a substance through the area of skin. 33.The method of claim 30 further comprising extracting analyte through thearea of skin.
 34. A method for producing homogenous cavitation at anarea of skin comprising: providing an ultrasound source to apply anultrasonic wave to the area of skin; positioning a screen between thearea of skin and the ultrasound source, the screen having a number ofopenings therein; and, applying ultrasound to the area of skin throughthe screen; wherein the openings in the screen nucleate cavitation andfilter cavitation bubbles by size thereby producing a homogenous bubblepopulation.
 35. The method of claim 34 further comprising delivering asubstance through the area of skin.
 36. The method of claim 34 furthercomprising extracting analyte-through the area of skin.
 37. Anultrasound device comprising: an ultrasound horn; and a housing for saidultrasound horn, a portion of said housing having a reduced insidediameter relative to a diameter of said horn; a screen positionedbetween an area of skin and the ultrasound horn, the screen having anumber of openings therein; wherein the reduced inside diameter focusesultrasonic energy on a small area of skin; and
 38. The ultrasound deviceof claim 37, wherein said reduced inside diameter is located near theskin.
 39. The ultrasound device of claim 37, further comprising acoupling medium contained in said housing.